PROJECT SUMMARY Since 2012 when the first human case of Middle East respiratory syndrome coronavirus (MERS-CoV) was confirmed, the World Health Organization has reported >2220 human infections and almost 800 deaths spread across 27 countries located in the Middle East, Europe, Asia, and the United States. Although dromedary camels are the known reservoir of the virus, there is limited knowledge on the mechanisms and factors associated with camel-to-human transmission, which remains the primary mechanism of human infections. Human outbreaks and the number of documented cases of MERS-CoV continue to grow in the Middle East and Asia; however there have, to date, been no documented cases of human disease in the eastern Africa countries where >65% of the world?s dromedary camels are found. This is despite evidence of prevalent MERS-CoV infection of camels in the region. The absence of human disease in East Africa may be explained by viral plasticity resulting in inefficient transmission and/or weakened virulence, or poor disease surveillance and reporting among the marginalized camel-owning nomadic pastoralist populations that inhabit remote arid lands of the regions. We will test these hypotheses by conducting integrated longitudinal cohort studies within a closed community of nave pastoralists and their camel population that is known to sustain MERS-CoV circulation in Marsabit County, Kenya, in order to determine the maintenance and transmission of the virus among camels, zoonotic transmission to humans, and severity of human infections. To determine if the circulating MERS-CoV is genetically and phenotypically distinct from known virus clades in the Middle East and Asia, we will isolate the East African virus by collecting samples biweekly from an infant cohort (birth -1 year) of 211 camels, followed by culture and isolation of the virus to performed genotypic and phenotypic comparison with the known clade viruses To investigate whether a combination of weak surveillance and poor access to health care are responsible for absence of disease, we will follow-up for a year, a cohort of 573 camel handlers through biweekly visits, weekly telephone calls, and access to a toll-free number in order to intensively examine and test them for MERS-CoV disease. In addition, we will identify, test, and follow-up >4500 in- and out-patients with respiratory illness at Marsabit County Referral Hospital for 3 years. To assess the risk the virus poses to humans, we will determine the level of viral shedding in camels, and relate this to the incidence of zoonotic transmission, and types of camel contact that increase transmission risk. These studies will identify the type of virus circulating in East Africa, increasing knowledge about plasticity of MERS-CoV and its impact on zoonotic transmission and disease. By elucidating the frequency and mechanisms of zoonotic transmission, and progression to clinical human disease, we will define the risk the virus poses to this community at the frontline of a newly emergent virulent virus by virtue of their occupation and lifestyle, paving the way for development of improved surveillance and appropriate prevention and control strategies.